Menopause is associated with about a 10-15 pound weight gain and a redistribution of fat to the abdomen. The increase in abdominal fat, also known as visceral fat is known to produce cytokines that cause inflammation which can lead to the metabolic syndrome. The metabolic syndrome represents a major public health burden because it increases the risk of cardiovascular disease, and promotes insulin resistance and diabetes. In the US, an estimated 25% of the population (50 million people) is classified as having this condition, which has led to enormous health care expenditures. There is evidence that estrogens in the form of hormone therapy (HT) can reduce abdominal fat accumulation. Estrogen replacement therapy has been found to decrease body fat mass as well as intra-abdominal and intrapelvic fat in postmenopausal women. Unfortunately, HT has a major drawback in that it causes proliferation of breast and endometrial cells. Clearly, estrogens that retain their beneficial effect on fat accumulation, but do not promote cell proliferation and cancer will have a profound impact on postmenopausal women. A key to developing safer estrogens for HT is to target specific estrogen receptors (ER) in various tissues. There are two ER subtypes, ERa and ERb. Studies indicate that the beneficial effect of estrogens on fat accumulation is mediated by ERa. Similarly, the stimulatory effects on breast and endometrial cells are mediated by ERa. Molecular studies have found that a variety of transcription factors and coregulatory proteins are required for ERs to regulate genes and produce biological effects. We hypothesize that;despite both effects being mediated by ERa, some ERa agonists could have beneficial effects on fat accumulation without producing the stimulatory effects on cell proliferation. To test this hypothesis, we screened over 50 plant extracts used in Traditional Chinese Medicine for tissue selective ERa activity. We found that two plants had ERa activity using a luciferase reporter gene. Similar to estradiol, both plant extracts produced a reduction in body weight and abdominal fat in mice fed a high fat diet. However, unlike estradiol, both plants did not stimulate the proliferation of MCF-7 breast cancer cells, which is the cell line classically used to test for ERa-mediated proliferative effects. Furthermore, unlike estradiol, the plant extracts did not increase the weight of the uterus. These results indicate that the ERa activity of the plant extracts do not lead to cell proliferation. Our objective is to extend these findings to animal models by studying the effect of a range of doses of two plant extracts with ERa activity on the proliferation of mouse mammary epithelial and uterine cells, and human breast and endometrial cancer cells. We believe that if these pre-clinical studies show that ERa agonists do not cause the proliferative effects as estrogens used currently in HT on the mammary gland and uterus this could lead to a therapeutic breakthrough for preventing abdominal fat accumulation and the metabolic syndrome in postmenopausal women. PUBLIC HEALTH RELEVANCE: Many postmenopausal women have increased weight gain and fat redistribution to the abdomen, which can lead to the metabolic syndrome. There is evidence that estrogens in the form of hormone therapy can reduce abdominal fat accumulation and the metabolic syndrome, but the Women's Health Initiative trial found that hormone therapy increases the risk of breast cancer. Our goal is to discover estrogens that do not promote cancer, but retain the beneficial of estrogens on body weight and fat accumulation.